USE OF IL-12 TO INCREASE SURVIVAL FOLLOWING ACUTE EXPOSURE TO IONIZING RADIATION
The present invention is directed to methods of increasing survival following exposure to non-therapeutic radiation comprising administration of IL-12.
1 . A method for increasing the probability of survival in a subject, the method comprising administering at least one therapeutically effective dose of IL-12 to the subject following an acute exposure to non-therapeutic whole body ionizing radiation, wherein the subject's probability of survival is increased due to at least one or two effects selected from the group consisting of:
(a) stimulation of innate immunity effects;
(b) protection of the gastrointestinal tract;
(c), stimulation of hematopoiesis, and
(d) stimulation of antioxidant and anti-apoptotic effects.
2 . The method of claim 1 , wherein the subject is human.
3 . The method of claim 1 , wherein the stimulation of antioxidant and anti-apoptotic effects results from release of erythropoietin (EPO).
4 . The method of claim 1 , wherein the stimulation of innate immunity effects results from release of interferon-gamma.
5 . The method of claim 1 , wherein the probability of survival is further increased by the release of endogenous IL-12.
6 . The method of claim 1 , wherein the subject has a decreased probability of infection, a decrease in tissue damage, or a combination thereof, as compared to a subject exposed to the same level of non-therapeutic whole body ionizing radiation and who has not been given a dose of IL-12.
7 . The method of claim 1 , wherein IL-12 directly stimulates the innate immunity effects by binding to the IL-12 receptor on natural killer cells, macrophages, dendritic cells, or any combination thereof.
8 . The method of claim 2 , wherein the dose of IL-12 is less than about 300 ng/kg or less than about 100 ng/kg.
9 . The method of claim 1 , wherein the acute exposure to whole body ionizing radiation is the result of a nuclear event.
10 . The method of claim 1 , wherein the acute exposure is at least about 1.0 Gy.
11 . The method of claim 1 , wherein the acute exposure is less than about 3.0 Gy.
12 . The method of claim 1 , wherein the IL-12 is administered:
(a) between a range of about 6 hours to about 120 hours after the acute radiation exposure;
(b) between a range of about 6 hours to about 72 hours after the acute radiation exposure; or
(c) at about 6 hours, about 12 hours or about 24 hours after the acute radiation exposure.
13 . The method of claim 1 , wherein IL-12 is administered subcutaneously or intramuscularly.
14 . The method of claim 1 , wherein supportive care is given to the subject simultaneously or following the administration of IL-12.
15 . The method of claim 14 , wherein supportive care comprises one or more of the following:
(a) administration of one or more antibiotics;
(b) administration of one or more hematopoietic growth factors; and
(c) administration of a blood transfusion.
16 . The method of claim 15 , wherein the hematopoietic growth factors are selected from the group consisting of G-CSF, GM-CSF and EPO.
17 . The method of claim 1 , wherein the subject has a decreased need for a platelet transfusion, a decreased probability of sepsis, a decreased probability of hemorrhage, or any combination thereof, as compared to a subject exposed to the same level of non-therapeutic whole body ionizing radiation and who has not been given a dose of IL-12.
18 . A method for resorting hematopoiesis in a subject, the method comprising administering at least one therapeutically effective dose of IL-12 to the subject following an acute exposure to non-therapeutic whole body ionizing radiation, wherein the dose is administered at least 24 hours after radiation exposure and hematopoiesis is restored via activation of the IL-12 receptor on hematopoietic cells in the bone marrow.
19 . The method of claim 18 , wherein the hematopoietic cells comprise niche cells and stem cells.
20 . The method of claim 19 , wherein the niche cells comprise osteoblasts.
21 . The method of claim 18 , where the hematopoiesis is restored following activation of the IL-12 receptor on megakaryocytes.
22 . The method of claim 21 , wherein the megakaryocytes are immature.
23 . The method of claim 18 , wherein hematopoiesis is restored following activation of the IL-12 receptor on osteoblastic cells in the bone marrow, megakaryocyte cells in the bone marrow, hematopoietic stem cells in the bone marrow, or a combination thereof.
24 . The method of claim of claim 18 , wherein the therapeutically effective dose of IL-12 is administered between about 48 and about 120 hours following radiation exposure.
25 . The method of claim 18 , wherein the dose of IL-12 is less than about 100 ng/kg or less than about 300 ng/kg.